1. Field of the Invention
The present invention relates to a novel method of administering anti nausea and anti emetic agents and to novel dosage forms containing such agents adapted for nasal administration.
The invention provides a novel method of administering therapeutic agents that inhibit nausea and emesis in mammals induced by stimulation of either the chemoreceptor trigger zone or the emesis (or vomiting) center in the central nervous system. Such stimulation can be caused by afferent stimulation (e.g., tactile pharyngeal impulses, labrynthine disturbances, motion, increased intracranial pressure, pain, distention of viscera or psuchologic factors) or blood borne emetic substances (e.g., as seen during pregnance, cancer chemotherapy, uremia, radiation therapy, electrolyte and endocrine disturbances, or the presence of chemical emetic substances).
The invention further provides dosage forms of those agents which are adapted for nasal administration and which include solutions, suspensions, sustained release formulations, gels and ointments. The therapeutic agents include selected antihistamines, anticholinergics, piperazines, phenothiazines, substituted butyprophenes and metoclopramide.
2. Background Art
A number of anti nausea and anti emetic agents are already known. Such agents are widely used therapeutically, chiefly in the treatment of emesis and nausea, and certain of the agents in the treatment of vertigo, motion-sickness, hypersensitivity phenomena (anaphylaxis and allergy), rhinitis, sinusitis and gastroesophageal reflux disease. Unfortunately, many of these agents when used: [1] cause undesirable side effects, [2] are inefficiently and variably absorbed from current dosage forms, [3] are difficult or inconvenient to administer in the current dosage forms after the onset of emesis or nausea, and [4] have delayed onset of pharmacological activity when administered by current dosage forms. It has now been unexpectedly discovered that these pharmacologically active agents can be administered by nasal delivery to provide: enhanced bioavailability, minimized variations in blood levels more rapid onset of activity and reduced dosages when compared to most current methods of administration (e.g., oral, subcutaneous, intra-muscular or by way of suppository).
Nasal delivery of therapeutic agents has been well known for a number of years. See, for example, U.S. Pat. Nos. 4,428,883; 4,284,648 and 4,394,390; and PCT application International Publication No. WO83/00286. See also, Hussain et al, J. Pharm. Sci: 68, No. 8, 1196 (1979); 69 1240 (1980) and 69 1411 (1980).
The PCT document describes nasal compositions for the administration of scopalamine, a parasympathetic blocking agent but fails to teach or recognize that a therapeutic response can be elicited at a dosage level which is only a fraction of that normally employed.
It should also be mentioned that while nasal administration of certain therapeutic agents to mammals, especially humans is known it is not a necessary conclusion from such knowledge that all therapeutic agents can be usefully administered by this route. In fact it has been shown that many drugs cannot be usefully administered by the nasal route. It certainly is not a suggestion that the selected anti-nausea and anti-emetic compounds of this invention which are not parasympathetic blocking agents can be usefully administered nasally to achieve enhanced bioavailability and sustained therapeutic blood levels.